Stereoselectivity unsymmetrical ketones

The Horner-Wittig reaction of a-phosphoryl sulphoxides 442, which are chemically stable, results in the formation of a, -unsaturated sulphoxides 443 in high yields (equation 264). The reaction has been found to be non-stereoselective, mixtures of E and Z isomers being formed from aldehydes and unsymmetrical ketones . In the case of aromatic aldehydes this reaction can also be advantageously performed in a two-phase catalytic system even without the usual PTC catalysts (Table 24). Intramolecular Horner-Wittig reaction of a-phosphoryl-5-oxosulphoxides 444 leads to a, -unsaturated cyclic sulphoxides 445 (equation 265). Starting from optically active 0,0-... 

Ketone-aldehyde additions have been effected using TiCl4 in toluene.24 These reactions exhibit the same stereoselectivity trends as other titanium-mediated additions. With unsymmetrical ketones, this procedure gives the product from the more-substituted enolate.25... 

Fig. 14.34. Regioselective and stereoselective Baeyer-Villiger rearrangement of an unsymmetrical ketone with magnesium monoperox-ophthalate hexahydrate (in the drawing, Mg is omitted for clarity).

Geometrical stereoselectivity can often be achieved in the condensation of unsymmetrical ketones 8 with tosylhydrazine l,2 and this feature means Shapiro reactions direct from an unsymmetrical ketone 8 via E-9 lead to the less substituted vinyllithium 11. On the other hand, a sequential alkylation-Shapiro sequence from a starting symmetrical hydrazone 12 will reliably form the more substituted vinyllithium 14 via Z-9 Retention of Z stereochemistry in Z-9 is dependent on its re-use almost immediately on standing, for example, Z-9 (R = vinyl) equilibrates to an 85 15 ratio E Z-9J ... 

Cross aldol reaction between two different aldehydes and/or ketones without prior activation or protection should provide a straightforward methodology for the synthesis of aldols, Mahrwald recently reported that treatment of aldehydes with TiCU and NEta (or TMEDA) gives rise to syn- do reaction in good yields (Eqs 38 and 39) [141], This method was extended to the aldehyde-ketone cross aldol reaction catalyzed by TiCU [142], an advantage of which is that reaction occurs at the more encumbered a-position of unsymmetrical ketones, as illustrated in Eqs (40) and (41) [143], The use of aliphatic aldehydes instead of PhCHO usually reduced stereoselectivity. When TiCU was replaced by a catalytic amount of BuTi(0-/-Pr)4Li, the aldol reaction was followed by the Tischenko reaction [144], Methyl vinyl ketone trimerized to give a chlorinated cyclic product with TiCU [145],... 

The enantioselective total synthesis of the polysubstituted tetrahydrofuran (-)-citreoviral, the unnatural enantiomer, was synthesized by L.E. Overman et al. The Prins-pinacol rearrangement of an allylic 1,2-diol with an unsymmetrical ketone proceeded with high stereoselectivity. The jb/s(trimethylsilyl)-1,2-diol was condensed with the dimethyl acetal of the unsymmetrical ketone in the presence of catalytic amounts of TMSOTf, which yielded a nearly 1 1 mixture of the corresponding acetal and rearrangement product. The acetal was converted to the desired tetrahydrofuran product upon exposure to tin tetrachloride. 

Some unsymmetrical ketones show regioselectivity in favour of the less hindered side 29 is an impressive example as both sides of the ketone are primary with branching occurring on one side only at the P carbon atom.8 You are advised to consult the literature before planning a stereoselective synthesis with ketone enolates. 

Many different research groups have contributed to the collection of empirical data in Tables 6-21. In some cases where the results do not fit overall trends, there are differences between similar experiments due to troublesome experimental or structural variables. A few of the misfits are probably due to uncertain structural assignments, and many of the others correlate with experimental procedures in which the concentration of electrophilic byproducts or contaminants (lithium ion, hydroxyl groups, protic or Lewis acids) is not controlled. There are also some misfit cases among the reactions of unsymmetrical ketones, and in reactions where allylic, benzylic, or propargylic ylides are employed. However, the great majority of cases are well behaved and follow general patterns that are summarized in Table 22 and are discussed in the section on interpretation of stereoselectivity trends. 

SCHEME 2.5. Regio- and stereoselectivity of the proline-catalyzed a-electrophilic substitution of an unsymmetrical ketone, according to Seebach s model. 

Alkoxypropargylation. The ambident character of the propargylic anion, which may be in equihbrium with the aUenic form, is responsible for its limited use in synthesis. In general the structure and reactivity of the ambident anion depend on the nature of the substrate, the counter cation, and the solvent. There is also an erythro-threo stereoselectivity problem when alkylated propargylic anions react with aldehydes or unsymmetrical ketones. In contrast, the zinc and titanium reagents derived from the title compound possess the allenic structure and, upon reaction with aldehydes, lead almost exclusively to the )8-acetylenic alcohol (eq 1), presumably by a chelate transition state (Sei process). The reaction also leads preferentially to the erythro diastereomer. The stereoselectivity is highest with titanium as the metal and THE as the solvent. ... 

No stereoselectivity was observed in the formation of a 1 1 diastereomeric mixture of 2-hydroxy-2-phenylethyl p-tolyl sulfoxide 145 from treatment of (R)-methyl p-tolyl sulfoxide 144 with lithium diethylamide . However, a considerable stereoselectivity was observed in the reaction of this carbanion with unsymmetrical, especially aromatic, ketones The carbanion derived from (R)-144 was found to add to N-benzylideneaniline stereoselectivity, affording only one diastereomer, i.e. (Rs,SJ-( + )-iV-phenyl-2-amino-2-phenyl p-tolyl sulfoxide, which upon treatment with Raney Ni afforded the corresponding optically pure amine . The reaction of the lithio-derivative of (-t-)-(S)-p-tolyl p-tolylthiomethyl sulfoxide 146 with benzaldehyde gave a mixture of 3 out of 4 possible isomers, i.e. (IS, 2S, 3R)-, (IS, 2R, 3R)- and (IS, 2S, 3S)-147 in a ratio of 55 30 15. Methylation of the diastereomeric mixture, reduction of the sulfinyl group and further hydrolysis gave (—)-(R)-2-methoxy-2-phenylacetaldehyde 148 in 70% e.e. This addition is considered to proceed through a six-membered cyclic transition state, formed by chelation with lithium, as shown below . ... 

Bordeau and coworkers have described an efficient and stereoselective synthesis of kinetic silylenol ethers. Less highly substituted silylenolates are regiospecifically prepared in high yield, around room temperature under kinetic conditions, from unsymmetric cyclic ketones and [(DA)2Mg] in THF/heptane (equation 68). 

On the other hand, when this reaction was carried out with 1-chlorovinyl p-tolyl sulfoxide derived from unsymmetrical dialkyl ketone 167 with Af-lithio 1-aminonaphthalene (entries 7 and 8), Z-ortho-alkenylated arylamine Z-171 was obtained as the main product from both vinyl sulfoxides with low stereoselectivity. The stereospecificity and stereoselectivity mentioned above are explained from the high configurational stability of the magnesium carbenoids generated from 1-chlorovinyl p-tolyl sulfoxides derived from a,/ -unsaturated ketones. 

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